Rectal artesunate as pre-referral treatment for severe malaria in sub-Saharan Africa: still a long way to go
Authors: Manfred Accrombessi, Jackie Cook
Journal: The Lancet Global Health (2022)

Rectal artesunate for pre-referral treatment of severe malaria has been reported as an effective malaria intervention to substantially reduce the risk of death and permanent disability among children younger than 5 years in sub-Saharan Africa, by delaying the progression of disease severity as children seek to access health facilities for adequate treatment.1Gomes MF Faiz MA Gyapong JO et al.Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial.Lancet. 2009; 373: 557-566Summary Full Text Full Text PDF PubMed Scopus (164) Google Scholar However, although well accepted as an intervention,2Awor P Kimera J Athieno P et al.Acceptability of pre-referral rectal artesunate for severe malaria in children under 5 years by health workers and caregivers in the Democratic Republic of the Congo, Nigeria and Uganda.Malar J. 2022; 21: 322Crossref PubMed Scopus (5) Google Scholar reported findings have raised concerns over the effectiveness of rectal artesunate in real-life conditions, which are often associated with shortcomings in terms of referral and quality of care.3Hetzel MW Okitawutshu J Tshefu A et al.Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.BMC Med. 2022; 20: 343Crossref PubMed Scopus (10) Google Scholar In addition, the target population for this strategy is children younger than 6 years, and in order to be effective, the administration of rectal artesunate must be followed by immediate transfer to an appropriate health facility with an intensive care unit, and a full 3-day regimen of artemisinin-based combination therapy (ACT) should be given once the child can tolerate oral medication. Unfortunately, those guidelines are often insufficiently adhered to, with low referral completion and neglected post-discharge treatment with ACT.4Brunner NC Omoluabi E Awor P et al.Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.BMJ Glob Health. 2022; 7e008346Crossref PubMed Scopus (10) Google Scholar Therefore, WHO recommended a moratorium on pre-referral rectal artesunate treatment and has sought a formal evidence review for developing detailed guidance on the conditions under which the use of this strategy can be implemented safely and effectively.5WHOThe use of rectal artesunate as a pre-referral treatment for severe P. falciparum malaria.https://www.who.int/publications-detail-redirect/9789240042513Date: 2022Date accessed: November 15, 2022Google Scholar The WHO decision to withhold further deployment of rectal artesunate has been castigated by some public health stakeholders.6Watson JA Warsame M Peto TJ et al.Stopping prereferral rectal artesunate—a grave error.BMJ Glob Health. 2022; 7e010006Crossref Scopus (8) Google Scholar Moreover, access to, demand for, and uptake of rectal artesunate have been limited among national malaria control programmes, health-care providers, and caregivers.7Inthavilay S Franchard T Meimei Y Ashley EA Barennes H Knowledge and acceptability of the rectal treatment route in Laos and its application for pre-referral emergency malaria treatment.Malar J. 2010; 9: 342Crossref PubMed Scopus (10) Google Scholar, 8Simba DO Kakoko DC Warsame M et al.Understanding caretakers' dilemma in deciding whether or not to adhere with referral advice after pre-referral treatment with rectal artesunate.Malar J. 2010; 9: 123Crossref PubMed Scopus (24) Google Scholar Given the emergence and spread of antimalarial resistance, and concerns raised so far, additional evidence such as cost-effectiveness, cost-savings, acceptability, and challenges outside clinical trial conditions are still required for safe and sustainable implementation of rectal artesunate. In The Lancet Global Health, Mark Lambiris and colleagues9Lambiris MJ Venga GN Ssempala R et al.Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints.Lancet Glob Health. 2022; (published online Dec 21.)https://doi.org/10.1016/S2214-109X(22)00507-1Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar examined the real-world costs and constraints to rectal artesunate implementation in three African countries (Uganda, Nigeria, and the Democratic Republic of the Congo). They highlighted that the potential benefit of rectal artesunate is limited by weak and under-financed health system components. The largest baseline constraints encountered were irregular health worker supervision, inadequate referral facility worker training, and limited malaria commodity supplies. They identified that health-care provider training and behaviour change campaigns were the largest startup costs, while the majority of the annual routine costs were attributed to supervision and supply chain management. To conclude, Lambiris and colleagues suggested that sustained essential health system investments over the long term are the key cornerstone to implement rectal artesunate as a preventive strategy to reduce mortality related to severe malaria in sub-Saharan Africa. This study is another reminder of how far we are from successful implementation of rectal artesunate in sub-Saharan African settings with poorly resourced health systems. However, the success of this strategy as well as many other malaria interventions mainly depends on the health priorities of political decision makers. Essential investment efforts should be focused on the readiness of primary health facilities and health workers by ensuring availability of pre-referral antimalarial medications, appropriate training, supportive supervision, and regular audits of the entire referral process.10Amboko B Machini B Githuka G Bejon P Zurovac D Snow RW Readiness of the Kenyan public health sector to provide pre-referral care for severe paediatric malaria.Trop Med Int Health. 2022; 27: 330-336Crossref PubMed Scopus (3) Google Scholar A strong and well adapted operational linkage between community health workers (CHWs) and referral facilities should also be established, allowing rapid detection of severe cases and ensuring appropriate transport to the facility. Moreover, social behaviour change communication could help promote acceptance and adherence to pre-referral treatment and practices by CHWs and caregivers. There is now an urgent need for updated, accurate, and feasible guidelines from WHO for rectal artesunate implementation in sub-Saharan Africa. These guidelines should be integrated with routine health community activities. Rectal artesunate as a pre-referral treatment is an important additional malaria strategy which can result in reduced malaria mortality and could help accelerate the progress towards elimination of malaria. There are several large, but not insurmountable, challenges along the cascade of the health-care pyramid for pre-referral rectal artesunate. Strengthening health system capability and capacity (training of CHWs, adequate drug supply, emergency transport availability) and repeated behaviour change campaigns are crucial determinants for successful and sustained rectal artesunate implementation. In order to mitigate concerns regarding the development of drug resistance, future research evaluations should also consider or develop alternative rectal or spray antimalarials, particularly combination therapies, for pre-referral treatment for severe malaria. In the meantime, while waiting for updated guidelines from WHO, countries should consider adopting and deploying this important strategy, while working to ensure it is implemented effectively. We declare no competing interests. Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraintsAlthough rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. Full-Text PDF Open Access